6-halo-3,5-seco-a-nor-steroids

ABSTRACT

6-HALO-4-OXA-3-OXO-ANDROSTANES ARE PREPARED VIA HALOGENATION OF 3,5-SECO-A-NOR-3-OIC ACIDS FOLLOWED BY LACTONIZATION. END-PRODUCTS ARE USEFUL AS ANTI-ANDROGENS.

United States Patent 01 ice 3,576,849 6-HALO-3,S-SECO-A-NOR-STEROIDSMilan Radoje Uskokovic, Upper Montclair, N.J., assignor to Holfmann-LaRoche Inc., Nutley, NJ.

No Drawing. Continuation-impart of application Ser. No.

680,308, Nov. 3, 1967. This application Sept. 13, 1968, Ser. No. 759,794

Int. Cl. C07c 69/14, 69/24 US. Cl. 260-488 6 Claims ABSTRACT OF THEDISCLOSURE 10 6-halo-4-oxa-3-oxo-androstanes are prepared viahalogenation of 3,5-seco-A-nor-3-oic acids followed by lactonization.End-products are useful as anti-androgens.

RELATED APPLICATIONS This application is a continuation-in-part of Ser.No. 680,308, filed Nov. 3, 1967, now abandoned.

DETAILED DESCRIPTION OF THE INVENTION This invention relates tocompounds of the formula HsC 0R1 Vn H306? H O H wherein R is hydrogen,lower alkyl or lower alkanoyl,

R is hydrogen or lower alkyl, V is an unsaturation between the land2-positi0n and n is a whole integer from O to 1, and A is selected fromone of the groups.

wherein R R and X are as above.

Another preferred embodiment of the present invention relates tocompounds of the formula wherein R R and X are as above withrepresenting identical halogens.

As used herein the term lower alkyl comprehends straight or branchedchain saturated hydrocarbon radicals such as methyl, ethyl, isopropyland the like. Similarly, the term lower alkanoyl indicates moieties derived from lower alkane carboxylic acids such as acetic acid, propionicacid and the like. The term halogen comprehends bromine, chlorine andfluorine.

The compounds of Formula I can be prepared via treatment ofcorresponding 3,5 seco-A-nor-androstan-3-0ic acids of the formulawherein R and R have the same meaning as above to insert one or twohalogen atoms in the 6-position. The starting materials of Formula IIare members of a known class of compounds which can be obtained byozonolysis of corresponding androst-4-en-3-ones. Monohalogenation viaa-keto halogenation can be effected by means known per se (cf., SteroidReactions, Djerassi, 1963, Holden- Day, Inc., especially Chapters 3 and4). For example, treatment of a compound of Formula II with bromine orchlorine to produce the corresponding 6-bromo or 6- chloro compound canbe effected at room temperature or below, for example, between 30 C. androom temperature. Preferably the reaction is conducted between 12 C. androom temperature. The reaction should be conducted using an amount ofbromine or chlorine equimolar to the amount of starting material ofFormula II. Moreover, the reaction should be conducted in an inertsolvent wherein the starting material of Formula II is soluble. Suitablesolvents are, for example, ether/ acetic acid, ether/ chloroform,dioxane/acetic acid, chloroform, carbon tetrachloride, aceticacid/hydrochloric acid and the like.

Monohalogenation of the compound of Formula II yields a6-halo-3,S-seco-A-nor-androstan-3-oic acid of the formula III wherein RR and X have the same meaning as above.

Patented Apr. 27, 1971. i

Compounds of Formula III can be converted to compounds of Formula Iwherein X is bromine or chlorine via means known per se, for example, bytreatment with an alkali metal borohydride, such as sodium or lithiumborohydride to reduce the 5-oxo moiety to a S-hydroxy moiety. Thetreatment with alkali metal borohydride can be effected, for example,below room temperature, at a temperature from the freezing temperatureof the solvent to room temperature (suitably in an ice bath), preferablyin an inert solvent, suitable solvents being lower alkanols, such asmethanol, ethanol or isopropanol, tetrahydrofuran, dioxane,dimethylformamide or the like. Following the reduction, acidificationeffects cyclization, i.e., lactonization. This lactonization can beeifected using organic acids such as acetic acid or mineral acids suchas hydrochloric acid. The acid can be directly added to the cooledreaction mixture subsequent to the alkali metal borohydride reduction orthe S-hydroxy compound can be isolated and then acidified to effectlactonization, which can be effected at or below room temperature, i.e.,from the freezing point of the solvent system to room temperature.

Compounds of Formula I where X is fluorine may be prepared fromcompounds of Formula HI where X is bromine or chlorine by a substitutionreaction. The substitution is effected by treatment of the Formula IIIcompound or most desirably with a lower alkyl ester thereof, with afluorine salt such as, for example, silver, potassium or lithiumfluoride. A particularly preferred embodiment utilizes silver fluorideas the fluorine salt. In a preferred embodiment the Formula III compoundis initially converted to the corresponding lower alkyl ester byconventional methods prior to substitution. For example, the methylester is conveniently prepared from the Formula III acid by reactionwith diazomethane in a manner known per se.

The substitution reaction is carried out in the presence of an anhydrousinert organic solvent in which both the reactants are soluble. Suitablesolvents include for example, dimethylsulfoxide, acetonitrile, ketonessuch as acetone and methyl ethyl ketone and dimethyl formamide. Whilethe reaction temperature is not critical, it is most desired that thereaction be run at the reflux temperature of the reaction medium.Acceleration of the reaction rate can be obtained by the addition of asmall amount of water to the reaction medium such as, for example, about2 ml. of H 0 per gram of ester compound.

The 6-fluoro seco ester obtained is saponified by treatment with aqueousbase in a lower alkanol, e.g., aqueous methanolio NaOH at roomtemperature. Lactonization of the resulting 6-fluoro seco acid as aboveresults in the desired 6-fluoro compound of Formula I.

In another aspect of the above substitution reaction a 6-bromoseco acidof Formula 111 is converted to the corresponding chloro compound ofFormula III by treatment with a chloride salt, e.g., lithium chloride.The solvent medium employed is the same as previously described for thehalogen substitution reaction above. This substitution embodiment may beconducted at a temperature of from about room temperature to the refluxtemperature of the reaction medium, with temperatures at about theformer level being preferred.

Halogenation of starting materials of Formula II can also be effectedby, for example, treatment of the compound of Formula IIwit'h sulfurylbromide or chloride to yield the corresponding 6,6-dihalo compound(Formula II) which is then dehydrohalogenated to yield the corresponding6-halo-6-ene compound (Formula II) which then, upon treatment withalkali metal borohydride as described above, is hydrogenated and thenlactonized. The intermediate Formula III compound can optionally behalogen exchanged prior to lactonization to thus yield the Formula Icompound.

Alternatively, the 6,6-dihalo compound (Formula II) may be directlyconverted into a compound of Formula I by lactonization in the mannerpreviously described 4 herein. This reaction scheme is illustrated bythe following partial formulas:

H3O I H3O /5 i. 5 r'r (II) x x (11') 1130 h AYR O X (III) X! I H3O T meI e s a 1'1 q n O o/ HOOC H 5 I 1') X 7 11") 4C1 L'r (III) I? wherein Xand X have the same meaning as above.

The above-described halogenation can be performed according to meansknown per se, for example, the treatment with sulfuryl bromide orchloride can be conducted preferably at room temperature, or by heating,i.e., between room temperature and about 70 C., in the presence of asolvent system, such as carbon tetrachloride/acetic acid. Thedehydrohalogenation can be effected via heat ing at a temperaturebetween about C. and about C. in the presence of a lithium salt such asthe chloride or carbonate and dimethylformamide.

The compounds of Formula I can also be obtained via treatment ofcompounds of the formula HOOC IV a peracid to yield the corresponding5a,6a-oxido comgen chloride or hydrogen fluoride yields thecorresponding 6fl-halo-Sa-hydroxy compound of the formula HO t wherein RR and X have the same meaning as above.

This epoxide opening can be effected by means known per se, for example,in aqueous or non-aqueous medium at room temperature or with heating insolvents such as acetic acid, dioxane, acetone, chloroform, ethanol, orthe like. The compound of Formula V simultaneously lactc nizes to acompound of Formula I since the compound of Formula V is formed underacidic conditions. Dehydration of the compound of Formula V thus yieldsa compound of Formula I.

In another route of obtaining compounds of Formula I, a compound ofFormula IV is directly subjected to treatment with halogen, such asbromine or chlorine, in a suitable inert organic solvent, such as carbontetrachloride, methanol or the like. This treatment can conveniently beeffected at room temperature or below room temperature.

The compounds of Formula IV can be prepared by dehydrating the 5-hydroxycompound obtained by reduction of a compound of Formula II. Thereduction of the compound of Formula II can be effected under nonacidicconditions by catalytic hydrogenation or by treatment with alkali metalborohydride as described above. The dehydration can be effected forexample via conversion to the 5- tosyloxy compound, followed bytreatment with collidine or dimethylforrnamide at elevated temperatureup to about 150 C. to effect dehydrotosylation. These reactions are alsoknown per se.

In another embodiment of the present invention compounds of Formula Iwherein n is 0 are treated with an oxidizing agent so as to yieldcompounds of the following formula X is bromine, R is hydrogen and R ismethyl in Formula VI above.

Products of Formula I wherein R is hydrogen can be converted to productsof Formula I wherein R is lower alkanoyl via conventional loweralkanoylati'on means, for example, by treatment with acetic anhydride inpyridine.

6 Prior to the alkali metal borohydride treatment it is advantageous tohydrolyze an intermediate wherein R is lower alkanoyl to thecorresponding compound wherein R is hydrogen. This hydrolysis can beeffected according to known means, for example, by alkaline hydrolysissuch as by treatment with aqueous sodium hydroxide.

Additionally, compounds of Formula I wherein R is lower alkanoyl can beobtained from a starting material corresponding to Formula II, butwherein R is represents an alkyl group, preferably tert-butyl, which issubjected to the treatments described above for the introduction of a6-halo substituent and for effecting cyclization, the alkyl groupthereafter being replaced by lower alkanoyl by conventional means, forexample by treatment with a lower alkanoic acid, e.g., acetic acid, inthe presence of hydrogen bromide.

End-products of Formulae I, I, I and VI are useful as anti-androgens. InFormulae I, I and VI, the substituents at the asymmetric centers atpositions 8, 9, l0, 13, 14 and 17 are shown in a specific opticalconfiguration whereas the substituents at the asymmetric centers atpositions 5 and 6 are not shown in a specific optical configuration.This invention includes compounds of these formulae having each of thepossible optical configuration at positions 5 and 6, i.e., fourdifferent enantiomers, as well as the racemates. It should be noted,however, that not each of the four possible enantiomers necessarilypossesses usefulness as an anti-androgen. For example, 6oc-brOIn0-17j3-hydroxy-l7a-methyl-4-oxa-androstan-3-one of Formula I, i.e., the5u,6a-enantiomer, is useful as an anti-androgen, whereas such usefulnesshas not been found for the other three enantiomers of this compound. Thenon-endocrinologically useful enantiomers of any particular compoundare, however, useful in that the enantiomers are intraconvertible. Thus,one A/B-trans enantiomer can be converted to the other A/B-transenantiomer, for example, a 5 06,606-61'13I1l1l0fi181 can be converted tothe Saba-enantiomer via equilibration in the presence of a bromide ion,for example, via treatment with lithium bromide or sodium bromide.Similarly, the A/B-cis enantiomers can be intraconverted. Moreover, theSB-enantiomers can be hydrolyzed under alkaline conditions, such as,with aqueous sodium hydroxide, to yield the corresponding 3,5-seco-A-nor-5-ol-3-oic acid which can be oxidized, for example, by chromiumtrioxide in the presence of acetic acid/methylene chloride to thecorresponding 3,5-seco-A-nor-5-oxo-3- oic acid which then can belactonized as described herein to yield the A/B-trans enantiomer, i.e.,the Sat-enantiomer, which, if desired, can be equilibrated to yield theother A/B-trans enantiomer.

As indicated above, the compounds of Formulae I, I, I and VI are usefulas anti-androgens. Where applicable the compound can be administered inthe form of the racemate or in the form of the enantiomer or enantiomerswhich possess the anti-androgenic activity. It is preferred toadminister the specific enantiomers which possess the anti-androgenicactivity. These compounds inhibit the effect of androgens uponandrogen-responsive organs. The anti-androgenic activity is shown, forexample, by administering to each of five castratemale rats, weighingapproximately 40-50 grams, concurrent injections of the compound insesame oil at 5 mg./0.2 mL/rat/day, and testosterone propionate at 0.1mg./ 0.2 ml./rat/ day by separate injection. A control group of fiverats should receive the testosterone propionate alone. After seven daysof treatment all animals are autopsied and weights of their seminalvesicles and prostates are determined. In-

hibition of the effect of testosterone'propionate on the. target organsshows activity. Besides inhibition of an-drogenic response totestosterone propionate, anti-androgenic ample, orally or parenterally.Dosage should be adjusted to individual needs. The active ingredient ofFormulae I, I, I and VI can be administered in conventional solid andliquid pharmaceutical dosage forms such as capsules, tablets,suppositories, solutions, suspensions, creams or the like. They cancontain conventional pharmaceutical additive such as stearyl alcohol,cetyl alcohol, petrolatum, polyalkylene glycols, water, :carnauba wax,lactose, corn starch, calcium stearate, talc or the like. They can besubmitted to conventional pharmaceutical expedients such assterilization or the like and can contain preservatives, emulsifyingagents, agents for the adjustment of osmotic pressure and the like.

The following examples are illustrative but not limitative of theinvention. All temperatures, unless otherwise stated, are in degreescentigrade. Compounds having a proton at an asymmetric carbon atom atposition-5 bear such proton in the 5a-stereo-configuration unlessexplicitly denoted as having a Sfi-stereo-configuration.

EXAMPLE 1 To a solution of 12.88 g. of 17,8-hydroxy-17a-methyl-5-oxo-3,5-seco-A-norandrostan-3-oic acid in 150 ml. of glacial aceticacid and 1500 ml. of anhydrous ether, stirred and cooled in an ice bath,was added 2 ml. of acetic acid saturated with hydrogen bromide. This wasfollowed after five minutes by dropwise addition of 21 ml. of 33%bromine in acetic acid diluted with 200 ml. of ether. The dropwiseaddition took about one hour and its rate was synchronized with the rateof decoloration of the added bromine in the reaction mixture. To theso-obtained re action mixture, with continued stirring and cooling, wasadded in portions 1700 ml. of 2 N aqueous sodium carbonate. Then thereaction mixture was transferred into a separatory funnel, shaken well,and the carbonate layer separated. The ethereal layer was washed threetimes, each time with 100 ml. of aqueous 2 N sodium carbonate. Thecarbonate liquors were combined, and after addition of ice, acidified topH 1 with concentrated hydrochloric acid. After standing one hour, theprecipitated acid was collected by filtration, washed well with water,and dried in an oven at 45. This gave crude6fi-bromo-17fi-hydroxy-17a-methyl-5-oxo-3,5-seco-A-norandrostan 3 oicacid, melting point 192194.

EXAMPLE 2 To a solution of 17 g. of crude65-bron1o-17fl-hydroxyl7ot-methyl-5-oxo-3,5-seco A norandrostan 3 oicacid (prepared as in Example 1) in 540 ml. of methanol, was added 51 ml.of 1 N sodium hydroxide solution, and the reaction mixture was left atovernight. It was then neutralized with 51 ml. of 1 N hydrochloric acidand diluted with three liters of water. The precipitated acid wasseparated by filtration, washed with water and dried in an oven at 45This gave crude 6e-bromo-17B-hydroxy-l7a-methyl-5-oxo 3,5seco-A-norandrostan-3-oic acid which upon repeated recrystallizationsfrom methanol melted at 201-2025"; [a] 13.7 (c.=0.59 in tetrahydrofuran)taken on automatic polarimeter, and [M --18.2 (c.=1 in tetrahydrofuran)taken on a classical polarimeter.

EXAMPLE 3 To a solution of 10.3 g. of crude6,8-bromo-17fi-hydroxy-17a-methyl oxo-3,5-seco-A-norandrostan-3-oic acid(prepared as in Example 1) in 350 ml. of methanol, stirred and cooled inan ice-bath, was added in portions during 20 minutes g. of sodiumborohydride. Stirring and cooling was continued for an additional hour.The reaction mixture was then acidified with concentrated hydrochloricacid to pH ca. 1, and after minutes evaporated in vacuo to a smallvolume. It was diluted with 250 ml. of water and extracted with oneliter of ether. The ethereal extract was washed three times, each timewith 50 ml. of 2 N aqueous sodium carbonate, then dried with anhydrousmagnesium sulfate, and evaporated to dryness. This gave a syrupyresidue, which after crystallization and several recrystallizations fromether gave 6,8- bromo-17fl-hydroxy-17e-methy1 4 oxa-androstan-3-one,melting point 163-174 (decomposition). [M -9.6 (c.=0.39 in methanol).

EXAMPLE 4 To a solution of 21 g. of crude 6a-bromo-17 8-hydroxy- 17ccmethyl 5 0x0 3,5-sec0-A-norandrostan-3-oic acid (prepared as in Example2) in 700 ml. of methanol, stirred and cooled in an ice-bath, was added21 g. of sodium borohydride in portions during 30 minutes. Afteraddition was complete, the reaction mixture was stirred and cooled foran additional hour, and then acidified to pH 1 with concentratedhydrochloric acid. The resulting suspension was reduced in vacuo to 200ml. volume, diluted with 600 m1. of water, and extracted three times,each time with 500 ml. of ether. The ethereal extract was washed twicewith 50 ml. of 2 N aqueous sodium carbonate and then twice with ml. ofwater, then dried with anhydrous magnesium sulfate and evaporated todryness. The residue crystallized on trituration with ether. As shown bythin layer chromatography, this product contains as major components6a-bromo-l7fi-hydroxy-17amethyl 4 oxo-androstan-3-one and6a-bromo-17fl-hydroxy-17a-methy1-4-oxo-5fl-androstan-3-one. Thesecompounds were separated from the crude product by fractionalcrystallization using acetone as solvent.

6a-bromo-17fl-hydroxy-17a-methyl-4 oxa androstan- 3-one is unstable onprolonged heating. This influences its melting point, which wasdetermined on a kofler hot stage. When put on stage at room temperatureand heated slowly, then it melted with decomposition at 202- 204. Whenput on stage at then it melts and decomposes at 213213.5, after atransformation at 207. When put on stage at 210, then it melts anddecomposes at 223-2235", and when put on stage at 220", then it meltsand decomposes at 226226.5, M1 -+93.2 (c.=0.68 in tetrahydrofuran).

6a bromo hydroxy-l7u-methyl-4-Oxa-SB-androstan-3-one melts at 192.5-"(with decomposition). [M 92 (c.=0.525 in tetrahydrofuran).

EXAMPLE 5 A suspension of 7.5 g. of6oa-bIO1I1O-17fl-hYdIOXY-170cmethyl-4-oxa-5/3-androstan-3-one and 30 g.of zinc dust in 700 ml. of absolute ethanol was stirred and refluxed for48 hours. Thin layer chromatography of the reaction mixture showed atthis time that no more starting material was present. The reactionmixture was filtered and the filtrate evaporated. The residue wasdissolved in 225 ml. of methanol, and after addition of 45 ml. of 1 Naqueous potassium hydroxide, was left overnight at room tempera ture.Next morning it was filtered and evaporated. The residue was taken up in300 ml. of water, made acidic to pH 1 with concentrated hydrochloricacid, and extracted in 1200 ml. of ether. The ethereal solution wasextracted four times, each time with 50 ml. of 2 N aqueous sodiumcarbonate, and then twice with 50 ml. of water. The combined carbonateand water layers were poured in icy concentrated hydrochloric acid, andthe precipitated 17 3-hydroxy-17ot-methyl-3,5-seco-A-norandrost 5en-3-oic acid was separated by filtration, washed with water and driedin the oven at 40. After recrystallization from ether, it melted at179.5-181.5. [M 46.6 (c. 0.9 in tetrahydrofuran) EXAMPLE 6 To a solutionof 1.532 g. of 17B-hydroxy-l7a-methyl- 3,5 seco-A-norandrost 5 en-3-oicacid in 100 ml. of methanol, stirred at room temperature, was addeddropwise 50 ml. of 0.1 M solution of bromine in carbon tetrachloride,and then the reaction mixture was diluted with 1 liter of ether. Theresultant solution was washed twice with 100 ml. of 2 N aqueous sodiumcarbonate, twice with 100 ml. of water, then dried with anhydrousmagnesium sulfate and evaporated. It gave a noncrystalline residue,which was chromatographed on a 1500 g. silica gel column. The fractionseluted with ethyl acetate were combined, and after evaporation gavecrystalline 6(3- bromo 17B hydroxy 17a methyl 4 oxa 55- androstan 3 one.After recrystallization from ether, it transformed above 175, and itmelted with transformations between 189-192", [04], 41.5 (c.=0.905 intetrahydrofuran) EXAMPLE 7 A mixture of l g. of6a-brom0-l7/8-hydroxy-17amethyl 4 oxa 5,8 androstan 3 one and 0.1 g. ofanhydrous sodium acetate in 10 ml. of acetic anhydride was refluxed for2 hours and then evaporated to dryness in vacuo. To the residue wasadded water and the mixture left overnight at room temperature. It wasthen extracted with 500 ml. of ether, the ethereal extract was washedthree times, each time with 25 ml. of 2 N aqueous sodium carbonate, andthen twice with 25 ml. of water, then dried over anhydrous magnesiumsulfate and evaporated to dryness. The noncrystalline residue waschrmatographed on a 300 g. silica gel column, and the fractions elutedwith 15% ethyl acetate in benzene were combined and gave crystalline 17Bacetoxy 60c bromo 17amethyl 4 oxa 5,8 androstan 3 one. This materialwhen twice recrystallized from ether melted at 187188.5, [0:1 80.7(c.=1.485 in tetrahydrofuran).

In the same manner 17;? acetoxy 6oz bromo 170cmethyl 4oxa-androstan-3-one is prepared from 60;- bromo 17p hydroxy 17oz methyl4 oxa androstan- 3-one.

EXAMPLE 8 To a solution of 2.27 g. of 17 3 acetoxy-5-oxo-3,5-seco-A-norandrostan-3oic acid in a mixture of 135 ml. of carbontetrachloride and 15 ml. of glacial acetic acid was added 1.6 ml. ofsulfurylchloride, and the reaction mixture was then stirred at roomtemperature for 19 hours. The solvent was removed in vacuo, and theresidue was dissolved in ether. The ethereal solution was extracted with2 N sodium carbonate. The carbonate layer was acidified withconcentrated hydrochloric acid, and the resultant suspension extractedwith methylene chloride. This extract was washed with water, dried overanhydrous sodium sulfate and evaporated. The so-obtained crude 17pacetoxy 6,6 dichloro 5 oxo 3,5-seco-A- norandrostan 3 oic acid wasdissolved in 50 ml. of methanol, and after addition of 12.2 ml. of 1 Npotassium hydroxide, the reaction mixture was stirred 5 hours at roomtemperature. It was then diluted with water, washed by shaking withether, and acidified with concentrated hydrochloric acid. The resultingsuspension was extracted with methylene chloride, the extract was washedwith water, dried and evaporated. The so-obtained crude 6,6- dichloro17B hydroxy 5 oxo 3,5 seco A- norandrostan 3 oic acid was recrystallizedfrom methanol and upon repeated recrystallizations from methanol meltedat 190-192.5; [M 77.5 (c.=1, in CHCl EXAMPLE 9 To a solution of 1.72 g.of 6,6-dich1oro-17fl-hydroxy- 5-oxo-3,5-seco-A-norandrostan-3oic acid in100 ml. of dimethylformamide was added 3.58 g. of lithium carbonate, andthe reaction mixture was then stirred and heated at 100 for 22.5 hours.After cooling to room temperature, the reaction mixture was diluted withether and extracted with 2 N sodium carbonate. The carbonate layer wasacidified with concentrated hydrochloric acid, and extracted withmethylene chloride. This extract was washed with water, dried overanhydrous sodium sulfate and evaporated. The residue was chromatographedon preparative thin layer plates. The product so-obtained, after tworecrystallizations from acetone-hexane, gave 6- chloro 175 hydroxy 5 0x03,5 seco-A-norandrost- 10 6-en-3-oic acid, melting point 1895-1925 51.4"(c.=l, in CHCl EXAMPLE 10 To a solution of 1 g. of 6 chloro 17Bhydroxy-5- oxo-3,S-seco-A-norandrost-6-en-3-oic acid, stirred and cooledin an icebath, was added in portions 1 g. of sodium borohydride during30 minutes. The reaction mixture was then stirred and cooled for anadditional hour, acidified with 5 ml. of concentrated hydrochloric acidand left for two hours at room temperature. After dilution with 1 literof methylene chloride, it was washed twice with 50 ml. of 2 N sodiumcarbonate, then with water, dried and evaporated. The residue wasdissolved in a mixture of 5 ml. pyridine and 5 ml. acetic anhydride, andleft at room temperature for 72 hours. It was then evaporated in vacuo.The residue was washed with water and after drying it was crystallizedfrom ether giving crystals which after repeated recrystallizations fromacetone gave 17/3- acetoxy 6oz chloro 4 oxa 515 androstan 3 one, meltingpoint 293-300 (with decomposition). [0;]; -53.8 (c.=0.55 intetrahydrofuran).

The mother liquors were purified by chromatography on a silica gelcolumn, and after recrystallization from acetone-ether (1:10) gave 17,8acetoxy 6 8 chloro- 4-oxa-androstan-3-one, melting point 17-8181. [M-+11.9 (c.=1.05 in tetrahydrofuran).

EXAMPLE 11 A mixture of 1.002 g. (0.004 mole) of 6B-bromo-17/3- hydroxy17a methyl 5 oxo-3,5-seco-A-norandrostan- 3-oic acid and 1.065 g. oflithium chloride in 35 ml. of dimethylsulfoxide was stirred at roomtemperature for 3 days. The reaction mixture was then diluted with 1.5l. of ether, washed with water (4X 100 ml.), dried over anhydrousmagnesium sulfate and evaporated. The residue, consisting of crystallinematerial was recrystallized from acetone to give 600 chloro 17,8 hydroxy170a methyl- 5-oxo-3,S-seco-A-norandrostan-3-oic acid, M.P. 231- 233.5(with decomposition); [M 18.1 (c.=1.03 in tetrahydrofuran).

EXAMPLE 12 17B hydroxy 17oz methyl 5 oxo 3,5 seco-A- norandrostan-3-oicacid (30 g.) was dissolved with heating in 300 ml. of glacial aceticacid, the stirred solution was cooled to room temperature, 3 ml. ofacetic acid saturated with hydrogen chloride (gas) was added followedimmediately by 98.9 ml. (1.06 equiv. of 1.00 molar) of chlorine inacetic acid (over 5 min.). After another 5 minutes the colorlesssolution was diluted with 1300 ml. of H 0 and cooled in an ice-bath for30 minutes. The solid was collected, washed with H 0, and dried in vacuoat The above substance (29.4 g.) in 490 ml. of methanol was cooled toca. +3", ml. of cold, 1 N sodium hydroxide solution was added and themixture was allowed to remain at +3 for 3.5 hours. Cold 1 N hydrochloricacid ml.) and H 0 (980 ml.) were added, the mixture was cooled in anice-bath for 0.5 hr., filtered and washed with cold methanol/H O (1:1)and cold acetone. The product 6a-chloro-1713-hydroxy-17a-methyl-5-oxo-3,5-sec.-A-norandrostan-3oic acid after drying at 90 had a melting pointof 218221 (dec.) 20.5 (in tetrahydrofuran, c.=1.0).

EXAMPLE 13 A 1 1., three-neck, round bottom flask, equipped with an airstirrer, 250 ml. dropping funnel, and calcium chloride drying tube wasflame-dried, charged with 1.0 g. of lithium borohydride in 100 ml. oftetrahydrofuran (previously filtered over Woelm neutral alumina,activity I; 10 ml. of tetrahydrofuran/1.0 g. of alumina), and cooled ina Dry Ice-acetone bath (75"). To this was added, over 0.5 hr., asolution of 10 g. of the 6oc-ChlOIO-S6CO acid prepared in Example 12 in200 ml. of tetrahydrofuran (filtered over alumina, as above). Thereaction was allowed to continue for 4 hours with cooling (75) andstirring. Excess hydride was then decomposed by the slow addition of 20ml. of H to the cold solution. The solution was adjusted to ca. pH 1 bythe addition of ml. of concentrated hydrochloric acid. After warming themixture to room temperature the tetrahydrofuran was removed in vacuo(35), and the residue was dissolved in 120 ml. of methylene chloride,200 ml. of H 0 was added, and the aqueous phase was extracted with two120 ml. portions of methylene chloride. The organic phase was Washedwith 200 ml. of sodium carbonate, two 200 ml. portions of H 0, 200 ml.of saturated sodium chloride solution, and dried (anhydrous sodiumsulfate). The white solid obtained after removal of the solvent in vacuo(60 bath) had an isomer distribution as determined by NMR analysis of5u,6u:5,8,6a 4.5. The isomers were separated by fractionalcrystallization from acetone.6a-chloro-l7B-hydroxy-17u-methyl-4-oxa-androstan-3one onrecrystallization from methylene chloride/ether and drying at 100 invacuo had a melting point of 199201 (turbid, clear at 203)variab1emelting point Z[OL]D25 +102.4 (c.=0.5 in tetrahydrofuran).6a-chloro-17fl-hydroxy-17a-methyl- 4-oxa-5p-androstan-3-one wasrecrystallized as above and dried at 105 in vacuo to yield needlesmelting at 204- 208 (sintering)variable melting point: [ad 91.0 (c.=0.5in tetrahydrofuran).

EXAMPLE 14 A suspension of 50 g. of6a-bromo-17/3-hydroxy-17amethyl-5-oxo-3,5-seco-A-norandrostan-3oic acidin 1 l. of ether was stirred and chilled in an ice-bath. This wastreated with a solution of diazomethane (from 100 g. ofN-nitrosomethylurea in a total of three 1 1. portions of ether) for 4hr. at ice-bath temperature and then overnight at room temperature. Theether solution was washed (1 l. of cold 5% sodium bicarbonate, 1 l. of H0), dried (sodium sulfate), and evaporated to give crude product. Theproduct was dissolved in 10 ml. of hot methylene chloride, the solventwas displaced with a total of 250 ml. of ether, and crystallizationoccurred from the hot solution; the final volume was ca. 125 ml. Theproduct,6a-bromo-17fi-hydroxy-17a-methyl-5-oxo-3,S-seco-A-norandrostan-3-oicacid methyl ester was collected after chilling overnight and dried at 70for 1 hr. The mother liquors, concentrated to 30 ml., aflorded anothercrop of the methyl ester. A sample was recrystallized from methylenechloride-ether and had a melting point of 124- 128; 16.S (in CHClc.=1.0).

EXAMPLE 15 ture was refluxed and stirred for23 hr. The reaction wasfollowed by tlc analysis. A brown precipitate was removed by filtration,most of the solvent was removed from the filtrate in vacuo (5560 theresidue was extracted with 750 ml. of ether (the aqueous phase was setaside) and the organicphase was washed with three 800 ml. portions of H0 and driedoversodium sulfate. The original aqueous phase was extractedwith 500 ml. of methylene chloride which was washed with 200 ml. of H 0,dried over sodium sulfate andcombined with the ether extract.Concentration of the" solvent yielded a yellow oil. The oil containing amixture, of isomers was dissolved in methylene chloride and filteredover a column of silica gel (120 g., Merck AG, 0.050.2 mm.):

Fraction: 7 I r Solvent 1 21. cH c1 2 2 l. CH Cl 3 2 l. CH Cl 4 21. 5%acetoneCH Cl 5 2 l. 5% acetone-CH Cl chloride and this organic phase wasdiscarded. Then the aqueous phase was acidified with 1 N hydrochloricacid and extracted with three 250 ml. portions-of methylenechloride/ether (2:1). The organic extract after being washed with 500ml. of H 0, two 250 ml. portions of saturated sodium chloride solution,and dried over sodiumsulfate, afforded 6a fluoro-17fi-hydroxyl7a-methyl-5- oxo-3,5-seco-A-norandrostan-3oic acid. This wascrystallized by solution in 300 ml. of hot acetone, boiling down to ca.125 ml., diluting with 25 ml. of warm petroleum ether (30-60) andchilling overnight at +3. The product began to crystallize from the hotsolution. A sample of product was recrystallized from acetone, dried invacuo and was found to have a melting point of 212- 2l5; [M 9.6 (intetrahydrofuran, c.=0.50).

EXAMPLE 16 6a fiuoro 17, 'hydl'OXy-17OL-II16thYl-5-OXO-3,S-SeCO-A-norandrostan-3-oic acid, 11.0 g., in tetrahydrofuran (220 ml.) wastreated with lithium borohydride (1.1 g.) in ml. of tetrahydrofuranexactly as described for the reduction of the chloro-seco acid inExample 13. The product was isolated by extraction with methylenechloride as already described; the organic extract was washed with 100ml. of cold, 5% sodium bicarbonate solution, and crude mixed isomerfiuoro-lactones was obtained, -l2.0 (in tetrahydrofuran, c.=O.50).

Fractional crystallization from acetone afforded the pure isomers. Ingeneral, the material was allowed to cool at room temperature for 2 hr.,the supernatant and washings were combined, and the product was dried invacuo (90). On recrystallization to the crude 6a-fluoro-17 3- hydroxy amethyl 4 oxa androstan 3 one having an of about +90 from methylenechlorideether and drying there were obtained crystals of M.P. 223- 228;+94.0 (c.=0.25 in tetrahydrofuran). Recrystallization of crude6a-fluoro-17B-hydroxy-17ometh yl-4-oxa-5fi-androstan-3one of [(11 ofabout 42 from acetone and drying yielded needles of M.P. 240- 248"(sintering from 235); 43.8 (c.=0.5 in

tetrahydrofuran.

7 EXAMPLE 17 A solution of 1.925 g. (0.005 mole) of 6a-bror'no-l7 3-hydroxy-17a-methyl-4-oxa-androstan-3one and 1.36 g. of2,3dichloro-S,6-dicyano-benzoquinone in 75,. ml. of.;anhydrous diioxanewas stirred and refluxed forfive 'da'ys. After addition of 0.68 g. of2,3dichloro-S,6adicyano-ben zoquinone, the stirring and refluxing wascontinuedlfor another 5 days. After cooling and filtration,thejfiltratfi' 13 EXAMPLE 18 To a stirred solution of 0.1 g. (0.0046mole) of lithium borohydride in 10 ml. of anhydrous tetrahydrofuran at-70 C., was added dropwise a solution of 1 g. (0.00265 mole) of6,6-dichloro-17B-hydroxy-5-oxo-3,S-seco-A-norandrostan-3-oic acid in 30ml. of anhydrous tetrahydrofuran. The stirring at -70 C. was continuedfor 4 hours. After addition of 2 ml. of water and 2 ml. of concentratedhydrochloric acid, the reaction mixture was stirred at room temperaturefor 1 hour. 'It was diluted then with l l. of ether, washed with water(25 ml.), 2 N aqueous sodium carbonate, and water (3X 25 ml.) again,then dried over anhydrous magnesium sulfate and evaporated. This gavecrystalline 6,6-dichloro-1713-hydroxy-4-oxa-androstan-3-one; M.P.238-239 (trans 235) after recrystallization from acetone/ether; [u]+53.2 (c.=0.87 in tetrahydrofuran). I

EXAMPLE 19 A 0.1% cream of 6oc-bI'OI1'10-17fi-hYdIOXY-17 u-methyl-4-oxa-androstan-3-one of the following formulation is prepared asdescribed:

. Mg. per gram 6a bromo 17,6 hydroxy-17a-methyl-4-oxa-androstan-3-one1.00 Stearyl alcohol 100.00 Cetyl alcohol 15.00 White petrolatum 70.00Methyl parahydroxybenzoate, U.S.P. 2.00 Propyl parahydroxybenzoate,U.S.P. 0.50 Isopropyl palmitate -3. 60.00 Polyoxyl 40 stearate, U.S.P40.00 Propylene glycol 120.00 Ethylenediaminetetraacetic acidtetrasodium salt (EDTA) 0.10 Distilled water 597.16

The stearyl alcohol, cetyl alcohol, petrolatum, propylparahydroxybenzoate, isopropyl palmitate and polyoxyl 40 stearate aremelted at 75. The mixture is cooled to and maintained'at 70. EDTA andmethyl parahydroxybenzoate are dissolved in hot distilled water to whichis added the propylene glycol. The solution is mixed at 7 5 and slowlyadded to the oil solution prepared previously, using slow agitation. Theresultant emulsion is gradually cooled with slow stirring. When thetemperature of the ointment reaches 55, a solution of6a-bromo-17fihydroxy-17a-methyl-4-oxa-androstan-3-one is added and mixedwith the ointment. When the temperature of the ointment reaches 50, coldwater is circulated in the jacket of the kettle and the ointment iscooled to 30 with stirring. The ointment is then transferred to storagecontainers.

EXAMPLE 20 A suppository formulation of 6a-bromo-l7 8-hydroxy- 17amethyl 4 oxa androstan 3 one is prepared as described:

Per 1.3 gm. suppository, gm. 6a -'br0mo17/3-hydroxy-l7a-methyl-4-oxa-andro- Refined synthetic cocoa butter(pharmaceutical grade) 1.250

Carnauba wax, 0.045

7 The cocoa butter and the carnauba wax are melted in a suitable'sizeglass lined container (stainless steel may also be used);"- mixed welland cooled to 45. 6u-bromo-17flhydroxy 17m 1methyl-4-oxa-androstan-3-one, which has been reduced to a fine powderwith no lumps, is added and stirred until completely and uniformlydispersed. The

mixture is poured into suppository molds to yield suppositories havingan individual'weight of 1.3 gms. The suppositories are cooled andremoved from molds. They are in- 14 dividually wrapped in wax paper forpackaging. (Foil may also be used.)

EXAMPLE 21 A tablet formulation of6u-bromo-17,8-hydroxy-l7amethyl-4-oxa-androstan-3-one is prepared asdescribed:

Per tablet, mg. 60; bromo 17,B-hydr0xy-l7a-methyl-4-oxa-androstan-3-one2.0 Lactose 121.5 Corn starch 70.5 Pregelatinized corn starch 8.0Calcium stearate 3.0

Total weight 205.0

600 bromo l7fi-hydroxy-17a-methyl-4-oxa-androstan- 3-one is mixed withthe lactose, corn starch and pregelatinized corn starch in a suitablesize mixer. The mix is passed through a comminuting machine fitted withNo. 1A screen and with knives forward. The mix is returned to the mixerand moistened with Water to a thick paste. The moist mass is passedthrough a No. 12 screen and the moist granules are dried on paper linedtrays at 110 F. The dried granules are returned to the mixer, thecalcium stearate is added and mixed well. The granules are compressed ata tablet Weight of 205 mg, using standard concave punches having adiameter of EXAMPLE 22 A capsule formulation of6Ct-bI'OII10-17,8-hydI'OXY-17wmethyl-4-oxa-androstan-3-one is preparedas described:

Per capsule, mg. 60c bromo 17,3 hydroxy 17u-rnethyl-4-oxa-androstan-3-one 5 Lactose 178 Corn starch 37 Talc 5Total weight 225 60c bromo 17B-hydroxy-17a-methyl-4-oxa-androstan- 3-oneis mixed with the lactose and corn starch in a suitable mixer. Themixture is further blended by passing through a comminuting machine witha No. 1A screen with knives forward. The blended powder is returned tothe mixer, the tale added and blended thoroughly. The mixture is thenfilled into No. 4 hard shell gelatin capsules on a capsulating machine.

EXAMPLE 23 DROXY-17a-MEIHYL-4-OXA-ANDROSTAN3 ONE IN OAS TRATED RATS Dose1 day Percent inhibition of an- 6a-bromo-17B Testosdrogenic responsehydroxy-17o;- terone Fluoxymethyl-4-oxapropio- Testosmes- SeminalVentral androstau-3- nate, meg. terone, terone, vesicles prostate one,meg. s.c. s.c. meg. s.c. meg. p.o.

Mll1igrams p.o.

15 EXAMPLE 24 To a solution of 18.2 g. of 17fl-tert-butoxy-5-oxo-3,5-seco-A-norandrostan-3-oic acid in 500 ml. of anhydrous ether, stirredand cooled in an ice-bath, was added 2 ml. of acetic acid saturated withhydrogen bromide. This was followed after two minutes by dropwiseaddition of 9 g. bromine diluted with 10 ml. of acetic acid. Theaddition took about twenty minutes and its rate was synchronized withthe rate of decoloration of the added bromine in the reaction mixture.The so-obtained solution was stirred and cooled for an additionalfifteen minutes, then transferred into a separatory funnel and washedfour times, each time with 700 ml. of water. The ethereal layer wasdried with anhydrous sodium sulfate and evaporated to dryness. This gavea syrupy residue which crystallized on trituration with hexane. Theproduct so obtained, after two recrystallizations from isopropyl ether,gave 63- bromo 17,8 tert-butoxy-5-oxo-3,S-seco-A-norandrostan- 3-oicacid, melting point 139-142 (decomposition), [th, 74 (c.=0.1 indioxane).

To a solution of 23.5 g. of the crude6,3-bromo-17fi-tertbutoxy-S-oxo-3,5-seco-Anorandrostan-3-oic acid in 100ml. of methanol, were added 60 m1. of 1 N sodium hydroxide solution and400 ml. of water. To the reaction mixture, stirred and cooled in anice-bath, was added portionwise over 10 minutes g. of sodiumborohydride. Stirring and cooling was continued for an additionalhour.The reaction mixture was then acidified with concentrated hydrochloricacid to pH ca. 1 and after minutes methanol was removed by evaporationin -vacuo. The water insoluble material was extracted with ether. Theethereal extract was washed three times, each time with 100 ml. ofwater, then dried with anhydrous sodium sulfate and evaporated todryness. The residue, on trituration with ether and cooling, yieldedsome crystalline material which gave after two recrystallizations frommethylene chlorideacetone 63-bromo-17fi-tert-butoxy-4-oxa-androstan3-one, melting point 193193.5, [111 (c.=0.1 in dioxane).

The noncrystalline residue was chromatographed on a 1200 g. florisilcolumn. The fraction eluted first with a total of 1 liter benzene and 5liter 1 percent acetone in benzene gave after evaporation crystalline6a-bromo-17/3- tert-butoxy-4-oxa-5fl-androstan-3-one. This material whentwice recrystallized from methylene chloride-isopropylether melted at192.5-193 (decomposition), [11],; 54 (c.=0.1 in dioxane). The secondfraction, eluted with a total of 41.1 percent acetone in benzene and31.5 percent acetone in benzene, yielded after evaporation crystalline6m-bromo-17fi-tert butoxy-4-oxa-androstan-3-one +124 (c.=0.1 indioxane). After two recrystallizations from methylenechloride-isopropylether this product melted at 185186 with rapiddecomposition and transformation to a solid material, which melted anddecomposed at 232235. A third fraction, eluted with a total of 3 l.methylene chloride gave after evaporation crystalline6,8-bromo-17,8-tert-butoxy-4-oxa-androstan-3-one with the abovementioned properties.

To a solution of 2.2 g. of the 6a-bromo-175-tert-butoxy-4-oxa-5fl-androstan-3-one in 40 ml. of acetic acid was added 10 m1. of33 percent hydrobromic acid in acetic acid. The solution was left atroom temperature for three hours, diluted with 700 ml. of ice water andthe water insoluble material extracted with methylene chloride. Theextract was washed with water, dried over anhydrous sodium sulfate andevaporated. After two recrystallizations from methylene chloride-ethylacetate, the crystalline residue gave17,6-acetoxy-6a-bromo-4-oxa-5fl-androstan-3-one, melting point 289-290(decomposition), -70 (c.=0.1 in dioxane).

To a solution of 3.3 g. of the Ga-bromo-17/3-tert-butoxy-4-oxa-androstan-3-one in 60 ml. of acetic acid was added 15 ml. of 33percent hydrobromic acid in acetic acid. The solution was left at roomtemperature for three hours,

r 16 3 diluted with 1000 ml. of ice-water and extracted with methylenechloride. The extract waswashed with water, dried over anhydrous sodiumsulfate and evaporated. After recrystallization from acetone, thecrystalline residue gave 17fi-acetoxy-6a-bromo 4 oXa-androstan-3-one,melting point 270-271 (decomposition( '+109 (c.=0.1 in dioxane).

To a solution of 2.2 g. of the 6B-bromo-17B-tert-butoxy-4-oxa-androstan-3-one in 40 ml. of acetic acid, was added 10 ml. of 33percent hydrobromic acid in'aceticacid-The' solution was left at roomtemperature for three hours, diluted with 700 ml. of ice-water andextracted with methylene chloride. The extract was washed with water,dried over anhydrous sodium sulfate and evaporated. After tworecrystallizations from ethyl acetate, the crystalline resi due gave17,8-acetoxy-6fi-bromo-4-oxa-androstan-3-one, melting point 192193(decomposition), [M 5 (c.=0.1 in dioxane).

What is claimed is:

1. A compound of the formula n is 0.

4. The compound of claim 1 wherein X is chlorine and n=1.

5. The compound of claim l'wherein R is methyl carbonyl.

6. A compound of the formula wherein R is hydrogen, lower alkyl or loweralkanoyl.

R is hydrogen or lower alkyl and X is bromine or chlorine.

References Cited UNITED STATES PATENTS 2,883,424 4/1959 Wildi 260+4883,047,615 7/1962 Nomine 260%88 3,251,860 5/1966 Pappo et al. 260514-;

LORRAINE A. WEINBERGER, Primary Examiner f I V. GARNER, AssistantExaminer "I U.S. Cl. X.R.

